The objective of this project is to establish vitamin D as a causal risk factor for multiple sclerosis (MS) by investigating how variation within regions o the genome important to vitamin D influence the onset and severity of MS. MS is an immune-mediated, demyelinating disorder caused by both genetic and environmental factors. Low serum levels of vitamin D are associated with MS risk, and with increased MS activity and severity. However, a causal relationship has not been firmly established: it is unclear whether low vitamin D level is a cause of MS or a result of it, and the biological mechanism underlying the association has not been determined. The overall hypothesis of this project is that low vitamin D is truly a cause of MS, and distinct genetic variants that either lead to lower overall serum vitamin D level or that cause dysregulation of genes governed by vitamin D serve to increase MS risk or severity. This project will utilize high-quality genotype data and a rich set of clinica characteristics from ~1,500 MS cases and ~12,000 controls to address three related hypotheses. The first hypothesis is that genetic variants previously found to be associated with low serum vitamin D level in genome-wide association studies will demonstrate a causal relationship with increased MS risk or severity, independent of other known genetic and environmental risk factors. A genetic instrumental variable analysis, adjusting for known confounders and genetic ancestry, will be utilized to estimate the causal effect of low vitamin D on MS. The second hypothesis is that an association will be observed between specific genetic variants in vitamin D pathway genes or in vitamin D response elements and increased MS risk or severity. Variants in genes that affect serum vitamin D level or that are affected by vitamin D will point to the biological mechanisms through which low vitamin D is acting to influence MS pathogenesis. Pathway analyses of these vitamin D genes and MS-associated genes will be conducted using the Disease Association Protein-Protein Link Evaluator (DAPPLE). The third hypothesis is that observed effects of vitamin D variants on MS risk and severity will be replicated in independent datasets of MS cases and controls, including in non-White populations. Analyses will be pursued in other datasets of MS cases and controls to confirm significant findings. The importance in MS susceptibility and severity of both genetic and environmental factors, including low vitamin D, will be demonstrated through this research and provide new insight into the etiology of this debilitating condition, as well as other conditions where a role for vitamin D is suspected.